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PubMed1987

Control of flux through the citric acid cycle and the glyoxylate bypass in Escherichia coli.

The glyoxylate bypass and citric acid cycle operate concurrently in Escherichia coli when acetate is the sole source of carbon and energy to sustain aerobic growth. The overall carbon balance allows fluxes through the central metabolic pathways (CMPs) to be computed on the assumption that these metabolic pathways are known. Acetate is fluxed via the CMPs to the precursors required for synthesis of new biomass and also to generate the reducing power and ATP required to convert these precursors to biomass. Under these circumstances, a junction is created at isocitrate where isocitrate lyase (ICL) and isocitrate dehydrogenase (ICDH) compete for their common substrate. In general, flux through ICL generates the precursors used for biosynthesis while the larger part of the flux (95%) through ICDH is dedicated to the supply of reducing power and ATP. The system sustains a large intracellular pool of isocitrate to accommodate the rather low affinity of ICL for this substrate. Excessive flux of isocitrate through ICDH is prevented by regulation of ICDH activity: reversible inactivation of ICDH is achieved by a bifunctional kinase/phosphatase, as the phosphorylated form of ICDH has no activity. The kinase/phosphatase responds to two classes of effectors--intermediates of the CMPs generated by flux through ICL and the lower energy forms of ATP and NADPH (ADP, AMP and NADP+) generated when these intermediates are used for biosynthesis. The effect is to adjust flux through ICDH so that the rate of supply of NADPH and ATP is equal to the demands of biosynthesis. Biosynthetic fluxes are limited by the rate of supply of precursors which depends on flux through ICL. Growth rate is most likely limited by the primary flux of acetate to acetyl-CoA or flux through ICL. In the steady state, the flux through ICDH is regulated to be twice the throughput of ICL. The evolution of this complex pattern of control may have depended on alternatives to the citric acid for energy generation.

Acetates↗
PubMed1981

Design of glycolysis.

The design of the glycolytic pathway resulting from the continuous refinement of evolution is discussed with regard to three aspects. 1. Functional and structural properties of individual enzymes. The catalytic constants of the glycolytic enzymes are remarkably optimized; the turnover numbers are within one order of magnitude. The same is true for the molarities of catalytic centres in the cytosol, as is noted for yeast. Functional properties of the enzymes are reflected in their tertiary and quaternary structures. 2. Regulatory mechanisms of single enzymes. A classification of the various types of enzymic control mechanisms operating in the glycolytic pathway is given. In addition to the usual Michaelis-Menten saturation kinetics and the various types of inhibition there is control by positive and negative effectors based on oligomeric structures (fast acting, fine control) as well as regulation by chemical interconversion structures (fast acting, fine control) as well as regulation by chemical based on enzymes cascades (slow acting, very effective). 3. Functional and regulatory mechanisms of the whole glycolytic reaction pathway. A prominent feature is the high enzyme:substrate ratio, which guarantees fast response times. However, a quantitative treatment of the overall kinetics is limited by an incomplete knowledge of the enzymes' dynamic and chemical compartmentation as well as some of their control properties. From an analysis of the oscillatory state, certain control points in the glycolytic chain can be located that coincide with major branching points to other metabolic pathways. These points are controlled by fast-acting cooperative enzymes that operate in a flip-flop mechanism together with the respective antagonistic enzymes, preventing futile cycles. The gating enzymes leading to the glycogen store and the citric acid cycle are of the slow-acting but very effective interconvertible type. The combination of all the complex and intricate features of design yields a glycolytic network that enables the cell to respond to its various metabolic needs quickly, effectively and economically.

Animals↗
PubMed1989

Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents.

More than 20 different cDNA clones encoding DNA-damage-inducible transcripts in rodent cells have recently been isolated by hybridization subtraction (A. J. Fornace, Jr., I. Alamo, Jr., and M. C. Hollander, Proc. Natl. Acad. Sci. USA 85:8800-8804, 1988). In most cells, one effect of DNA damage is the transient inhibition of DNA synthesis and cell growth. We now show that five of our clones encode transcripts that are increased by other growth cessation signals: growth arrest by serum reduction, medium depletion, contact inhibition, or a 24-h exposure to hydroxyurea. The genes coding for these transcripts have been designated gadd (growth arrest and DNA damage inducible). Two of the gadd cDNA clones were found to hybridize at high stringency to transcripts from human cells that were induced after growth cessation signals or treatment with DNA-damaging agents, which indicates that these responses have been conserved during mammalian evolution. In contrast to results with growth-arrested cells that still had the capacity to grow after removal of the growth arrest conditions, no induction occurred in HL60 cells when growth arrest was produced by terminal differentiation, indicating that only certain kinds of growth cessation signals induce these genes. All of our experiments suggest that the gadd genes are coordinately regulated: the kinetics of induction for all five transcripts were similar; in addition, overexpression of gadd genes was found in homozygous deletion c14CoS/c14CoS mice that are missing a small portion of chromosome 7, suggesting that a trans-acting factor encoded by a gene in this deleted portion is a negative effector of the gadd genes. The gadd genes may represent part of a novel regulatory pathway involved in the negative control of mammalian cell growth.

Amino Acid Sequence↗
PubMed1996

Effects of viral inhibitors of apoptosis in models of mammalian cell death.

Apoptotic cell death is used as a defence against infection by viruses. To counter this protective mechanism, some viruses carry genes whose products can inhibit progression of the apoptotic process in the host cell. As it is clear that the core cell death mechanisms have been conserved through evolution, viral genes from various sources can be used to unravel these mechanisms in mammalian cells. We have produced transgenic mice that express the cowpox gene crmA in their T cell compartment, and analysed their susceptibility to apoptosis. We have studied the effects of the baculovirus genes p35 from Autographa californica nuclear polyhedrosis virus and IAP from Orgyia pseudotsugata nuclear polyhedrosis virus on cell death induced in HeLa cells by over-expression of interleukin-1 beta converting enzyme (ICE), overexpression of the CD95-associated protein FADD, or cell death induced by treatment with TNF plus cycloheximide. These experiments indicate that viral anti-apoptosis proteins target both the activation and effector phases of the physiological cell death process.

Animals↗
PubMed1991

Glucose: a more powerful modulator of fructose 2,6-bisphosphate levels than insulin in human hepatocytes.

This study provides the first experimental evidence of the short-term control of fructose 2,6-bisphosphate (Fru(2,6)P2) levels in adult human hepatocytes. (1) In hepatocytes whose metabolic status resembles the fed state (glycogen-rich), exposure to glucagon (10(-8) M) caused a drastic decrease in the levels of this effector and a significant fall in lactate production rate. Adrenaline, isoprenaline (a beta-adrenergic agonist) and lactate exerted a similar action decreasing Fru(2,6)P2 concentration. (2) In glucagon pre-treated, glycogen- and Fru(2,6)P2-depleted cells (a situation that mimics the fasted state), Fru(2,6)P2 re-synthesis was strictly dependent on glucose availability. (3) Insulin did not seem to exert a direct action on the control of Fru(2,6)P2 in human hepatocytes. The hormone--which failed to enhance Fru(2,6)P2 in glucose-starved cells--did not further increase Fru(2,6)P2 content nor its time-course evolution as compared to hepatocytes incubated with glucose alone. (4) Lactate caused a significant delay in the glucose-induced increase in Fru(2,6)P2 content that could not be prevented by insulin. (5) Data indicate that in human hepatocytes glucose is a more powerful modulator of Fru(2,6)P2 than insulin, and that variations in blood lactate concentration may also play a role in the control of hepatic Fru(2,6)P2 levels during the fasted-to-fed transition in humans.

Cells, Cultured↗
PubMed1996

Immunotherapy for peritoneal ovarian carcinoma metastasis using ex vivo expanded tumor infiltrating lymphocytes.

Surgery and chemotherapy have contributed to a modest overall survival in patients with epithelial ovarian carcinoma. It is therefore important to pursue novel therapy strategies for this disease that are different from conventional chemotherapy. Tumor infiltrating lymphocytes (TILs) from patients with ovarian carcinoma may represent an active immune response of the host directed against the tumor cells. These TILs can be expanded in vitro in low concentrations of recombinant interleukin-2 (rIL-2) by a few thousandfold. The resulting T-cell lines comprise CD3+CD4+TCR alpha beta + or CD3+CD8+TCR alpha beta + cells, or mixtures of both. These T-cell lines may exhibit either tumor-specific cytotoxicity against autologous tumor cells, or produce cytokines (interferon-gamma, tumor necrosis factor, and granulocyte stimulating factor) either in antigen-dependent (tumor-specific) or an antigen-independent manner. T-cell lines exhibiting primarily autologous tumor-specific cytotoxicity were developed from approximately 50% of the patients. Blocking experiments using appropriate monoclonal antibodies revealed that the CD3/TCR complex on the effector cells and the MHC class I antigens on the tumor cells were involved in the cytolytic process. We have developed a four-step method for the expansion of TILs to large numbers (1 x 10(10) to 1 x 10(11)) sufficient for clinical trials in patients with ovarian cancer. We have conducted a pilot clinical trial to examine the feasibility and clinical effects of intraperitoneal TILs and low-dose rIL-2 in patients with advanced ovarian carcinoma who were refractory to platinum-based chemotherapy. More recently, procedures have been developed for obtaining large numbers of purified CD8+ rIL-2-expanded TILs for the treatment of patients with ovarian carcinoma. The evolution of clinical trials and correlative studies necessary to develop an effective adoptive immunotherapy approach were discussed.

Adoptive Transfer↗
PubMed1999

Immunology and biochemistry of Hymenolepis diminuta.

This review is an account of modern research into the immunology and biochemistry of the rat tapeworm, Hymenolepis diminuta. The first half of the review is devoted to the immunological responses of the host to the parasite. It describes the specific responses that occur when the host is exposed to a primary infection, and the changes that occur when further infections are superimposed on the primary one. The aquisition of immunity to the tapeworm and its persistence in the absence of the infection are also discussed, as well as the non-specific responses of the host to the parasite. The second half of the review is concerned with biochemistry, summarizing the early biochemical work that has been carried out on the tapeworm and describing the metabolic pathways now thought to be characteristic of the parasite. What little information that exists on intermediary metabolism in eggs and larvae is summarized here. Much of this section is concerned with the role of mitochondria in H. diminuta, especially the control of the critical branchpoint (PK/PEPCK), which partitions carbon into either the cytosol or the mitochondrion. The role of 5-hydroxytryptamine in controlling both worm behaviour and metabolism is discussed, followed by a brief look at some other effectors that may prove in the future to have great significance in regulating the parasite. Finally, there is a detailed consideration of strain variation within H. diminuta and of the impact on the tapeworm of components of the immune system, formerly described as the 'crowding effect'. The review concludes with a brief discussion of evolutionary aspects of the rat-tapeworm relationship and a comprehensive bibliography.

Animals↗
PubMed1991

[Rhino-sinusal immunology].

Nose and sinus pathology is frequently related to a chronic inflammation, the mechanisms of which involve different cell types that form the MALT, or effector cells. B-lymphocytes are three times more numerous than the T-lymphocytes, where the CD4+ cells predominate over the CD8+ cells. IgA's are mainly secreted by the plasmocytes. In IgA deficiency, a relative increase in IgG or IgD plasmocytes has been recorded. Antigenic information is obtained from cells presenting the antigen. Langerhans-like cells have been described. Two different populations of mast cells have been identified, whilst on the contrary eosinophilic cells are normally absent. The particularities of capillary vascularization and the extent of the nerve fibre network contribute to the creation of a micro-environment interacting with the lymphocytes. The phenomena of cellular interaction are described through the dynamic evolution of the IgE-dependent response in allergic rhinitis.

Humans↗
PubMed1998

Natural killer cell reactivity: activation and cytolysis mechanism models, involving heat shock protein, haemopoietic histocompatibility, major histocompatibility complex and complement molecules.

The close association of heat shock protein (HSP), haemopoietic histocompatibility (Hh), major histocompatibility complex (MHC), and complement genes on the same chromosomal region, and the fact that all these genes are inherited on the whole in each haplotype of an individual, might indicate some evolutionary and functional correlations among them. Several data suggest for HSP70 molecules a possible role as a molecular target recognizable by natural killer (NK) cells. HSP70 sequences from both prokaryotic and eukaryotic organisms reveal that about half of the amino acid residues are identical and many of the remaining residues are similar. I here assume that NK reactivity might start, early in the immunogenesis process, as a effect of the interaction between HSP70 molecules and a hypothetical HSP receptor of yet immature non-cytolytic NK cells. To this receptor, an HSP molecule might act as an activator or an inhibitor depending on whether its amino acid residues are reactive or not with it, respectively. Later in the immunogenesis process, murine Hh or human equivalent molecules, dominantly expressed in bone marrow target cells, might select the non-reactive NK clones of an individual, inducing them to mature and express a lytic machinery. As a consequence of the NK maturation, proliferating hemopoietic target cells expressing only or mainly activator HSPs on their surface might undergo NK cytolysis. This might explain the NK lysis of apparently normal cells found in human foetal marrow; moreover, this might explain in some way the F1 hybrid resistance phenomenon. The NK reactivity of an individual would be further modulated by the expression on the NK surface of particular receptors (CD94, p58) specific for defined MHC molecules (Cw1, Cw3, Bw6, B7) on the target cells. Such a specific interaction would induce an 'NK effector inhibition'. The NK reactivity mechanism might have been further evolutionarily modified and adapted by the involvement of other NK receptors, such as CD11b (specific for the C3b factor of the complement) and CD16 (specific for the IgG Fc piece). Cooperation among HSP, MHC, CD11b, CD16, C3b and Fc allows us to propose original models of the activation and cytolysis mechanisms in the NK cytotoxicity and antibody-dependent cell cytotoxicity phenomena.

Animals↗
PubMed1982

Characterization of H-2Db antigens implies haplotype differences in the number of H-2 molecules expressed.

Investigation of the molecular heterogeneity of H-2Db region antigens by using monoclonal antibodies and complex alloantisera has yielded evidence for the existence of only one gene product in this region. Sequential immunoprecipitation and isoelectric focusing analysis suggest that the private H-2.m2 and public H-2.m64 specificities defined by monoclonal or alloantibodies are present on the same molecule. Blocking studies with these reagents indicate these specificities represent two determinants spatially separated on the H-2Db molecule. Functional studies suggest that effector T cells may be generated against both of these determinants or closely associated epitopes, but the majority of the T cells recognize an epitope associated with or identical to the private specificity H-2.m2. Studies of the D region-encoded products of haplotypes besides H-2b have shown two or more distinct molecules can be detected by anti-H-2.m64 in both the H-2d and H-2q haplotypes. The presence of H-2.m64 on a single Db molecule is unique and gives further evidence for the lack of other gene products encoded in this region. Speculations based on the molecular heterogeneity of the D region gene products are made concerning the evolution and genetic organization of H-2 genes.

Animals↗
PubMed1998

The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor.

We have identified the yeast CRT1 gene as an effector of the DNA damage and replication checkpoint pathway. CRT1 encodes a DNA-binding protein that recruits the general repressors Ssn6 and Tup1 to the promoters of damage-inducible genes. Derepression of the Crt1 regulon suppresses the lethality of mec1 and rad53 null alleles and is essential for cell viability during replicative stress. In response to DNA damage and replication blocks, Crt1 becomes hyperphosphorylated and no longer binds DNA, resulting in transcriptional induction. CRT1 is autoregulated and is itself induced by DNA damage, indicating the existence of a negative feedback pathway that facilitates return to the repressed state after elimination of damage. The inhibition of an autoregulatory repressor in response to DNA damage is a strategy conserved throughout prokaryotic and eukaryotic evolution.

Animals↗
PubMed1998

Evolutionary variation of immunoglobulin mu heavy chain RNA processing pathways: origins, effects, and implications.

Immunoglobulins (Ig) can occur in two physical forms, soluble (secreted) and membrane bound. The soluble form is secreted from B cells, and is present in the blood and other fluids where it plays a role as an immune effector molecule. The membrane-bound form of the Ig molecule is inserted into the B-cell membrane, where it serves as a receptor for antigen. The function of the membrane-bound Ig as a receptor for antigen requires additional accessory molecules, the membrane Ig plus accessory molecules are referred to, collectively, as the B-cell receptor (BCR) complex. The secreted and membrane-bound forms of an Ig result from alternative patterns of RNA processing of the primary transcript from the heavy chain gene. IgM is the only class of Ig known to be conserved in all vertebrate species (perhaps exclusive of the agnathan fish). While the structure of the IgM heavy (mu) chain gene has been highly conserved in vertebrate evolution, the patterns of alternative RNA processing of the mu transcript show surprising diversity. In particular, the bony fish (teleosts) produce membrane mu-chain message by a splicing pathway that is quite different from that seen in other vertebrates; it results in the production of membrane IgM that lacks the C mu 4 domain. How this unusual RNA splicing pattern could have evolved and its implications for the function of the BCR in the bony fishes are considered here.

Animals↗
PubMed1983

The T-cell receptor mediating restrictive recognition of antigen.

Four facts characterize restrictive recognition of antigen. First, in large measure, allele-specific determinants on R are recognized when R is functioning either as a restricting element (RL) or as an allo-target (or even xeno-target) (RF). Second, there is a high frequency of virgin antigen-responsive t cells with alloreactivity, i.e. anti-RF. Third, there is a strict relationship between the class of effector function and the class of RL recognized (restrictive recognition of antigen, XF) but a relaxed relationship between class of effector function and class of RF recognized (alloreactivity). Fourth, the effector T cell functions anti-RL-dependently when XF is the target (restrictive recognition of antigen) and anti-RL-independently when RF is the target (alloreactivity). From these facts are derived the following conclusions. The T cell uses a dual recognitive, single receptor (Model I, Figure 1). A single germ-line VT locus specifying anti-allele-specific recognition of species R encodes both the anti-R and the anti-X combining sites. A "learning" process (occurring in the thymus) is required to establish the restriction specificity (anti-RL) as well as the effector function/class of RL relationship. The repertoire is derived by somatic mutation of all germ-line VT genes specifying anti-RF (Model IA, Table 3 and Figure 9). Given Model IA (Table 3 and Figure 9), we can account further for the existence of an extensive polymorphism of R and minimal polygeneism, for the high frequency of crossreactivity between anti-XF and RF, and for the physiology and genetics of cell-cell communication in immune responsiveness.

Animals↗
PubMed1978

Cytotoxic T-cell responses in mice infected with influenza and vaccinia viruses vary in magnitude with H-2 genotype.

Secondary effector T-cell populations generated by cross-priming with heterologous influenza A viruses operate only in H-2K or H-2D compatible situations, when assayed on SV40-transformed target cells infected with a range of influenza A viruses. The H2-Kb allele is associated with a total failure in the generation of influenza-immune cytotoxic T cells, though this is not seen for the primary response to vaccinia virus. In both influenza and vaccinia development of effector T cells operating at H-2Db is greatly depressed in B10.A(2R) (kkkddb) and B10.A(4R) (kkbbbb), but not in B10 (bbbbbb), mice. However, there is no defect in viral antigen expression at either H-2Kk or H-2Db in B10.A(2R) target cells. This apparently reflects some inadequacy in the stimulator environment, as (A/J X B6) F1 T cells can be induced to respond at H-2Db when exposed to vaccinia virus in an irradiated B6 but not in a B10.A(4R) recipient. The present report, together with the accompanying paper by Zinkernagel and colleagues, records the first rigorous demonstration of both a nonresponder situation and a probable Ir-gene effect for conventional infectious viruses. Possible implications for the evolution of H-2 polymorphism and mechanisms of Ir gene function are discussed.

Animals↗
PubMed1997

An evolutionarily conserved domain in a subfamily of Rabs is crucial for the interaction with the guanyl nucleotide exchange factor Mss4.

Mss4 is a guanine nucleotide exchange factor that specifically binds to, and promotes GDP-GTP exchange on, a subset of the Rab GTPases (Burton, J. L., Burns, M. E., Gatti, E., Augustine, G. J., and De Camilli, P. (1994) EMBO J. 13, 5547-5558). In order to identify the domain(s) of the GTPase that is important for this interaction, protein chimeras were constructed between Rab3a, which binds Mss4, and Rab5a, which does not bind Mss4. We have identified the amino-terminal portion of Rab3a as the Mss4-binding region, with the effector domain being critically required for binding and the flanking regions further enhancing the interaction. Sequence comparisons have revealed that Mss4-binding Rabs share more homology with each other than with Rabs that do not bind Mss4. The region of highest homology between these Rabs, which defines them as members of the same evolutionary branch within the Rab subfamily, coincides with the domain shown here to be critical for Mss4 binding. A mutation in the zinc-binding domain of Mss4 (Mss4 D96H), a region that is highly conserved between Mss4 and its yeast homologue Dss4, completely abolished its property to bind to, and promote GDP-GTP exchange on, Rab3a. Thus, the preservation of the Mss4/Dss4-GTPase interaction appears to have been a critical factor in the evolution of this subset of Rab proteins.

Amino Acid Sequence↗
PubMed1997

[Modulation of inflammatory cells in helminth infections].

In this review, different mechanisms by which helminthic parasites modulate the activities of inflammatory cells are considered. Examples are presented of parasitic products interfering with lymphocytes and their products such as antibodies, then modifying both regulation and effector response of the immune system. Furthermore, examples of interference on the complement system are illustrated. Parasites such as Ancylostoma caninum produce factors such as the neutrophil inhibitory factor (NIF) capable of inhibiting the neutrophil-endothelium adhesion, whereas Trichinella spiralis produces a glycoprotein, the 45gp, which inhibits different neutrophil functions. Parasites are also able to modulate the function of the monocytes-macrophages which in some infections play a crucial role; the modulation of NO synthesis is also relevant to the host-parasite relationship. Finally, the different anti-oxidant systems of helminthic parasites are described. The comprehension of such evasion mechanisms of the immune response is necessary to develop vaccines and new drugs, but it is also useful to clarify the contribution of parasites to immune system evolution.

Animals↗
PubMed1996

Identification of a novel Rac1-interacting protein involved in membrane ruffling.

The Rac GTP binding proteins are implicated in actin cytoskeleton-membrane interaction in mammalian cells. In fibroblast cells, Rac has been shown to mediate growth factor-induced polymerization of actin to form membrane ruffles and lamellipodia. We report here the isolation of a noval Rac1-interacting protein, POR1. POR1 binds directly to Rac1, and the interaction of POR1 with Rac1 is GTP dependent. A mutation in the Rac1 effector binding loop shown to abolish membrane ruffling also abolishes interaction with POR1. Truncated versions of POR1 inhibit the induction of membrane ruffling by an activated mutant of Rac1, V12Rac1, in quiescent rat embryonic fibroblast REF52 cells. Furthermore, POR1 synergizes with an activated mutant of Ras, V12Ras, in the induction of membrane ruffling. These results suggest a potential role for POR1 in Rac1-mediated signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed1983

Sequence homology between Lac and Gal repressors and three sugar-binding periplasmic proteins.

Many proteins consist of several independent folding units or domains, each specifying a different function. Repressor proteins such as Lac or lambda cI carry small N-terminal domains which recognize DNA sequences and larger C-terminal domains which are required for effector recognition and/or oligomerization. The native periplasmic metabolite-binding proteins consist of short membrane-recognizing signal sequences and larger C-terminal metabolite-binding domains which also recognize membrane-bound proteins involved in transport and chemotaxis. The DNA-recognizing domains of many repressors are homologous, as are the sugar-recognizing periplasmic proteins. Here I demonstrate that the sugar-binding domains of the Lac and Gal repressors are homologous with the sugar-binding domains of three periplasmic proteins.

Amino Acid Sequence↗